无菌性松动是人工关节置换术后远期失败的主要原因。既往研究证实人工关节周围界膜组织中的磨损颗粒诱导巨噬细胞凋亡，并与骨溶解及无菌性松动密切相关，抑制巨噬细胞凋亡，可以减轻骨溶解及预防假体松动。但目前研究的不足之处是巨噬细胞中凋亡信号的传导调控途径并未明确，特别是如何选择调控凋亡的关键靶点蛋白来治疗骨溶解和假体松动缺乏深入研究。本课题提出以下设想：磨损颗粒通过内质网应激途径和线粒体途径诱导巨噬细胞凋亡，其中GADD153/TRB3/AKT/Bad通路参与调控这两条途径之间的交叉应答，选择抑制GADD153/TRB3/AKT/Bad通路可以有效抑制巨噬细胞凋亡，预防骨溶解。课题通过临床病例发现现象，体外细胞实验证明机制及筛选靶点蛋白，体内动物实验证实治疗效果四部分内容验证以上设想。本课题的研究意义在于为预防治疗假体周围骨溶解及无菌性松动提供一种新的思路和方法，从而延长人工关节的使用寿命。

Aseptic loosening is a major cause of the failure of artificial joint replacement. Previous studies have confirmed that the apoptosis of macrophage is induced by wear particles within the interface membrane, and is associated with periprosthetic osteolysis and aseptic loosening. The inhibition of macrophage apoptosis can reduce osteolysis and prevent prosthesis loosening. However, the apoptotic mechanism of macrophage is still unclear, particularly there is a little study on the way of choosing a key target protein regulating apoptosis to treat osteolysis and prosthetic loosening . In this study, it is proposed that macrophage apoptosis is induced by wear debris through the ER stress pathway and mitochondrial pathway, in which GADD153/TRB3/AKT/Bad signaling is involved in the cross-talk. The inhibitation of GADD153/TRB3/AKT/Bad signaling could effetively inhibit macrophage apoptosis and prevent osteolysis. To verify this hypothesis, we investigate the clinical cases to find typical phenomenon, make cell experiments in vitro to prove its mechanism and identify target proteins, and make further animal experiments in vivo to confirm the treatment effect.The significance of this study is to provide a new idea and method for the prevention and treatment of periprosthetic osteolysis and aseptic loosening, thus extending the longevity of artificial joints.